The treatment of coronavirus-associated SARS has been evolving and so far there
is no consensus on an optimal regimen. This chapter reviews the diverse treatment experience and
controversies to date, and aims to consolidate our current knowledge and prepare for a possible
resurgence of the disease.

Treatment strategies for SARS were first developed on theoretical bases and from
clinical observations and inferences. Prospective randomized controlled treatment trials were
understandably lacking during the first epidemic of this novel disease. The mainstream therapeutic
interventions for SARS involve broad-spectrum antibiotics and supportive care, as well as antiviral
agents and immunomodulatory therapy. Assisted ventilation in a non-invasive or invasive form would
be instituted in SARS patients complicated by respiratory failure.

Anti-bacterial agents are routinely prescribed for SARS because its presenting
features are non-specific and rapid laboratory tests that can reliably diagnose the SARS-CoV virus
in the first few days of infection are not yet available. Appropriate empirical antibiotics are thus
necessary to cover against common respiratory pathogens as per national or local treatment
guidelines for community-acquired or nosocomial pneumonia (Niederman et al 2001). Upon
exclusion of other pathogens, antibiotic therapy can be withdrawn.

In addition to their antibacterial effects, some antibiotics are known to have
immunomodulatory properties, notably the quinolones (Dalhoff & Shalit 2003) and macrolides
(Labro & Abdelghaffar 2001). Their
effect on the course of SARS is undetermined.

SARS can present with a spectrum of disease severity. A minority of patients with
a mild illness recover either without any specific form of treatment or on antibiotic therapy alone
(Li G et al 2003; So et al 2003).

Various antiviral agents were prescribed empirically from the outset of the
epidemic and their use was continued despite lack of evidence about their effectiveness. With the
discovery of the SARS-CoV as the etiologic agent, scientific institutions worldwide have been
vigorously identifying or developing an efficacious antiviral agent. Intensive in vitro
susceptibility tests are underway.

The use of ribavirin has attracted a lot of criticism due to its unproven
efficacy and undue side effects (Cyranoski 2003). Ribavirin at non-toxic concentrations has no
direct in vitro activity against SARS-CoV (Huggins 2003; Cinatl et al 2003a; Health Canada July 2, 2003). Clinical experience
so far, including quantitative reverse transcriptase polymerase chain reaction (RT-PCR) monitoring
the nasopharyngeal viral load, has also not been able to suggest any substantial in vivo
antiviral effect from this drug (Peiris
et al 2003b). It is still a moot point as to whether or not the immunomodulatory actions of
ribavirin, as found in other conditions (Ning et al 1998; Hultgren et al 1998), could also play a
role in the treatment of SARS (Peiris
et al 2003b; Lau & So 2003).

The prevalence of side effects from ribavirin is dose-related. High doses often
result in more adverse effects, such as hemolytic anemia, elevated transaminase levels and
bradycardia (Booth et al 2003). However,
lower doses of ribavirin did not result in clinically significant adverse effects (So et al 2003). Side effects have also been
observed more frequently in the elderly (Kong et al 2003).

Oseltamivir phosphate (Tamiflu®, Roche Laboratories Inc., USA) is
a neuraminidase inhibitor for the treatment of both influenza A and B viruses. It was commonly
prescribed together with other forms of therapy to SARS patients in some Chinese centers. Since
there is no evidence that this drug has any efficacy against SARS-CoV, it is generally not a
recommended treatment apart from in its role as an empirical therapy to cover possible
influenza.

Lopinavir-ritonavir co-formulation (Kaletra®, Abbott Laboratories,
USA) is a protease inhibitor preparation used to treat human immunodeficiency virus (HIV) infection.
It has been used in combination with ribavirin in several Hong Kong hospitals, in the hope that it
may inhibit the coronaviral proteases, thus blocking the processing of the viral replicase
polyprotein and preventing the replication of viral RNA.

Preliminary results suggest that the addition of lopinavir-ritonavir to the
contemporary use of ribavirin and corticosteroids might reduce intubation and mortality rates,
especially when administered early (Sung
2003). It thus appears worthwhile to conduct controlled studies on this promising class of
drugs.

Interferons are a family of cytokines important in the cellular immune response.
They are classified into type I (interferon α
and β
, sharing components of the same receptor) and type II (interferon γ
which binds to a separate receptor system) with different antiviral potentials and immunomodulatory
activities.

So far, the use of interferons in the treatment of SARS has been limited to
interferon α
, as reported from China (Zhao Z et al
2003; Wu et al 2003; Gao et al 2003) and Canada (Loutfy et al
2003). The Chinese experiences were mostly in combining the use of interferons with immunoglobulins
or thymosin, from which the efficacy could not be ascertained. Faster recovery was observed
anecdotally in the small Canadian series using interferon alfacon-1 (Infergen®,
InterMune Inc.,
USA), also known as consensus interferon, which shares 88% homology with interferon α
-2b and about 30% homology with interferon β
.

In vitro testing of recombinant interferons against SARS-CoV was recently
carried out in Germany (Cinatl et al
2003b) using interferon α
-2b (Intron A®, Essex Pharma), interferon β
-1b (Betaferon®, Schering AG) and interferon γ
-1b (Imukin®, Boehringer Ingelheim). Interferon β
was found to be far more potent than interferon α
or γ
, and remained effective after viral infection. Although interferon α
could also effectively inhibit SARS-CoV replication in cell cultures, its selectivity index was
50-90 times lower than that of interferon β
. These in vitro results suggested that interferon β
is promising and should be the interferon of choice in future treatment trials.

Human gamma immunoglobulins were used in some hospitals in China and Hong Kong
(Wu et al 2003; Zhao Z et al 2003). In particular, an
IgM-enriched immunoglobulin product (Pentaglobin®, Biotest Pharma GmbH, Germany) was
tried in selected SARS patients who were deteriorating despite treatment (Tsang & Lam 2003).
However, as there was often concomitant use of other therapies such as corticosteroids, their
effectiveness in SARS remains uncertain.

Convalescent plasma, collected from recovered patients, was also an experimental
treatment tried in Hong Kong. It is believed that the neutralizing immunoglobulins in convalescent
plasma can curb increases in the viral load. Preliminary experience of its use in a small number of
patients suggests some clinical benefits and requires further evaluation (Wong et al 2003).

Recently, glycyrrhizin, an active component derived from liquorice roots, was
tested against SARS-CoV in vitro (Cinatl et al 2003a). It has previously been
used in the treatment of HIV and hepatitis C virus infections, and was found to be relatively
non-toxic with infrequent side effects (e.g. hypertension; hypokalemia). In Vero cell cultures, it
could inhibit the adsorption, penetration and replication of SARS-CoV, and was most effective when
administered both during and after viral adsorption. It has been postulated that the mechanisms are
mediated through the nitrous oxide pathway (Cinatl et al 2003a). However, as
glycyrrhizin can only act against SARS-CoV at very high concentrations, its clinical dosing and
utility remain uncertain. It could perhaps be explored as an adjunct therapy for SARS, or continued
as an ingredient or base in herbal preparations.

The rationale for using immunomodulatory therapy in SARS is based on the fact
that acute infections in general can stimulate the release of proinflammatory cytokines. In SARS,
there may be an excessive host response or cytokine dysregulation. This hypothesis may be
substantiated from the observation that clinical deterioration can paradoxically occur despite a
fall in the viral load as IgG seroconversion takes place (Peiris et al 2003b), as well as from
autopsy findings which demonstrate a prominent increase in alveolar macrophages with
hemophagocytosis (Nicholls et al
2003). A tri-phasic model of pathogenesis comprising viral replicative, immune hyperactive and
pulmonary destructive phases was thereafter proposed (Peiris et al 2003b; Sung 2003). Intuitively, immunomodulatory therapy
carefully applied during the hyper-immune phase may be an important treatment component in SARS.

Corticosteroids have been the mainstay of immunomodulatory therapy for SARS.
Their timely use often led to early improvement in terms of subsidence of fever, resolution of
radiographic infiltrates and better oxygenation, as described in many Chinese and Hong Kong reports
(Zhong & Zeng 2003; Xiao et al 2003; Wu et al 2003; Zhao Z et al 2003; Meng et al 2003; So et al 2003; Lau & So 2003; Lee et al 2003; Tsang & Lam 2003; Ho JC et al 2003). However, there is much
scepticism and controversy about the use of corticosteroids, centering on their effectiveness,
adverse immunosuppressive effects and impact on final patient outcomes.

An early Singaporean report on five patients on mechanical ventilation indicated
that corticosteroids showed no benefits (Hsu et al 2003). A retrospective series
of over 320 patients from a regional hospital in Hong Kong concluded that two-thirds progressed
after early use of ribavirin and corticosteroids, but only about half of these subsequently
responded to pulsed doses of methylprednisolone (Tsui et al 2003). A cohort study also noted
that about 80% of patients had recurrence of fever and radiological worsening (Peiris et al 2003b). This contrasted
with another paper which described four patient stereotypes for pulsed methylprednisolone therapy,
namely the good responder, good responder with early relapse, fair responder and poor responder. The
good responders were the most common group (Tsang & Lam 2003). There was also a comparative
study showing the efficacy and safety of pulsed methylprednisolone as an initial therapy compared
with a lower dosage regimen (Ho JC et al
2003). On the contrary, pulsed methylprednisolone was identified as a major independent
predictor for mortality (Tsang OTY et
al 2003).

The inconsistencies of treatment outcomes in SARS (or other illnesses) could be
due to differences in the timing, dosing and duration of corticosteroid use (Lau & So 2003;
Meduri & Chrousos 1998). The following points have been emphasized (So et al 2003; Lau & So 2003):

The timing of initiating corticosteroids should coincide with the onset of a
truly excessive immune response, which may be best represented by a combination of
clinico-radiographic surrogate criteria. Too early use of corticosteroids may theoretically prolong
the viral replicative phase and increase the viral burden, whereas delayed administration may not be
able to halt the cytokine storm and prevent immunopathological lung damage.

The dosage of corticosteroids should be chosen to sufficiently counterbalance
the degree of hyper-immunity. It should be adjusted to individual body weight and disease severity,
with the latter reflected by surrogate criteria before the immunological profile of SARS is fully
understood.

The duration of corticosteroids should be adequate to maintain the optimized
immune balance. Too short a course may result in a rebound of cytokine storm with lung damage,
whereas protracted usage will put the patient at risk of various corticosteroid
complications.

The ultimate aim should theoretically be to strike an optimal immune balance so
that the patient can mount a sufficient adaptive immune response to eradicate the virus, but without
the sequelae of irreversible lung damage from immune over-reactivity. A published protocol (Appendix
1) based on the above rationale was reported to have achieved satisfactory clinical outcomes (So et al 2003; Lau & So 2003).

Although corticosteroids can be beneficial, their use is not without risk.
Profound immunosuppression, resulting from needlessly high doses or protracted usage of
corticosteroids, not only facilitates coronaviral replication in the absence of an effective
antiviral agent, but also invites bacterial sepsis and opportunistic infections. There has been one
report of a SARS patient who died from systemic fungal infection (Wang et al 2003).

The common phenomenon of "radiological lag" (radiological resolution
lagging behind clinical improvement) must be recognized. As long as the patient remains clinically
stable, it is likely that an optimal immune balance has been reached, and most radiological
infiltrates will resolve gradually on a diminishing course of corticosteroids over 2-3 weeks. No
additional corticosteroids are necessary to hasten radiological resolution under such circumstances
(Lau & So 2003; Yao et al 2003).
Radiographic abnormalities arising from a superimposed bacterial pneumonia must also be
differentiated from the progressive immunopathological lung damage of SARS, since the latter would
result in adding further corticosteroids.

As superimposing infections add to the morbidity and mortality and offset the
beneficial effects of corticosteroids in SARS, it is of vital importance that strict control of
hyperglycemia during corticosteroid administration is implemented to reduce the chance of septic
complications (Van den Berghe et al 2001)
and measures are taken to prevent ventilator-associated pneumonia (Collard et al 2003). Successful control
of superimposing infections also demands a judicious use of empirical and culture-directed
antimicrobials.

In summary, corticosteroids must not be indiscriminately prescribed for SARS, but
should only be used according to the above principles and by exercising good clinical judgment.

Thymosin alpha 1 (Zadaxin®, SciClone Pharmaceuticals Inc., USA) is
used in the treatment of chronic viral hepatitis B and C, and has also been administered to SARS
patients in some Chinese hospitals (Zhao Z et
al 2003; Gao et al 2003). It is a
relatively safe product and may augment T-cell function. The role and effectiveness of this agent in
SARS has not yet been determined.

Despite treatment efforts, some SARS patients still develop acute hypoxemic
respiratory failure. According to the current literature, 20-30% of SARS warranted admission into
intensive care units, and 10-20% eventually required intubation and mechanical ventilation.

The initial management of SARS-related respiratory failure is oxygen
supplementation. If the oxygen saturation remains low or dyspnea persists, assisted ventilation,
either through non-invasive or invasive means, has to be considered.

Non-invasive ventilation (NIV) is instituted via a face or nasal mask, as
distinguished from invasive ventilation which necessitates endotracheal intubation. It is a valuable
treatment for acute respiratory failure of various causes, and can avoid complications associated
with intubation and invasive ventilation (Baudouin et al 2002; Peter et al 2002). Its application in SARS
may be of particular benefit since SARS patients are frequently treated with high dose
corticosteroids, which predispose them to infections including ventilator-associated pneumonia.

NIV can be given using a CPAP of 4-10 cm H2O or bi-level pressure
support with an inspiratory positive airway pressure (IPAP) of <10 cm H2O and an
expiratory positive airway pressure (EPAP) of 4-6 cm H2O. Contrary to the scenarios for
non-SARS-related acute respiratory distress syndrome, higher pressures were generally not necessary
and should be avoided whenever possible, because not only was there usually no additional clinical
improvement observed, but it can also add to the risk of pneumothorax and pneumomediastinum. The
latter conditions are known complications of SARS, even without assisted positive pressure
ventilation (Peiris et al
2003b).

Although NIV can improve patient outcome, the infective risks associated with
aerosol generation have hampered its use in many hospitals. Nevertheless, centers with experience
have reported the use of NIV to be safe, if the necessary precautions are taken (Li H et al 2003; Zhao Z et al 2003; Unpublished data from
Hong Kong). In addition to the recommended standard infection control measures for
aerosol-generating procedures (Centers for Disease Prevention and
Control [CDC] May 6, September
23, 2003; World Health
Organization [WHO] April 24, 2003), the
use of exhalation ports which generate round-the-tube
laminar airflow (e.g. Whisper Swivel II, Respironics Inc., USA) and viral-bacterial filters
interposed between the mask and exhalation port may further reduce the infective risk.

Patients with SARS-related respiratory failure who continue to deteriorate while
on NIV, or in whom NIV is contraindicated, should be promptly intubated and mechanically ventilated.
The actual endotracheal intubation procedure bears a high infective risk and healthcare workers must
strictly adhere to all infection control measures. To minimize the risk, the procedure is best
performed by highly skilled personnel (Lapinsky & Hawryluck 2003) using rapid
sequence induction. Other approaches like a "modified awake" intubation technique and
elective intubation upon recognizing signs of imminent need for airway management have been
recommended (Cooper et al 2003).

Most centers (Lew et al 2003; Gomersall & Joynt 2003) used ventilation
method and settings with reference to the strategies for acute respiratory distress syndrome (ARDS)
(The ARDS network 2000).
Both pressure and
volume control ventilation can be employed. The tidal volume should be kept low at 5-6 ml per Kg of
the predicted body weight, and plateau pressures be kept less than 30 cm H2O. Positive
end-expiratory pressure (PEEP) should also be titrated to as low as possible to maintain the
oxygenation, since a high rate (34%) of barotraumas have been reported (Fowler et al 2003). Mechanically ventilated
patients should be adequately sedated and a short-term neuromuscular blockade may be required for
permissive hypercapnia.

In this SARS epidemic, which eventually involved 8098 probable cases worldwide,
the overall case-fatality ratio has been updated to 9.6%. Significant regional differences were
seen. China had the greatest number (5327) of cases, but its case-fatality ratio was reported as
being only 7%. Hong Kong came second with 1755 cases, of whom 17% died. Taiwan, Canada and Singapore
followed, and their ratios were 11%, 17%, and 14% respectively (WHO September 23,
2003). Age-stratified ratios were estimated to be <1% in patients <
24 years old, 6% in 25-44 years old, 15% in 45-64 years old, and >50% in elderly >
65 years old (WHO May 7,
2003). The estimates in Hong Kong were 13% in patients <60 years old,
and 43% in those >
60 (Donnelly et al 2003).

In addition to age, death rates may be affected by other patient factors such as
genetic predispositions, the immune status, pre-existing co-morbidities and cardiopulmonary reserve,
and by the disease severity which depends theoretically on the viral strain's virulence, viral load
and magnitude of the host's immune response. The rates may also be related to other factors such as
case selection and volume, facilities and manpower, treatment strategies and regimens.

A multi-center study comparing four treatment regimens in Guangzhou, China, found
that a regimen (Appendix 2) of early use of higher dose corticosteroids, coupled with nasal
continuous positive airway pressure (CPAP) ventilation, produced the least mortality. All 60
clinically-defined SARS patients (mean age 30.5 years) treated with this regimen survived, 40% of
them used CPAP and none required mechanical ventilation. Only a small number of deaths were recorded
out of a further 160 cases treated with the same regimen (Zhao Z et al 2003).

Favorable protocol-driven treatment outcomes were also reported from a center in
Hong Kong. The protocol (Appendix 1) was applied to 88 consecutively admitted SARS patients (mean
age 42), of whom 97% were laboratory-proven cases. The overall mortality was 3.4% (3/88) occurring
in patients aged >
65 only, out of which two died from co-morbidities instead. 24% required intensive care unit
admission, 14% received non-invasive ventilation (bi-level pressure support) and 10% invasive
mechanical ventilation. High-resolution computed tomography performed 50 days after the commencement
of treatment showed that most survivors did not have clinically significant lung scarring, and none
required any form of pulmonary rehabilitation (Lau & So 2003).

Based on the treatment experiences of the above and other centers with similar
outcomes, suffice it to say that SARS may not be a disease of high mortality, at least in
non-elderly patients. Even though a substantial portion may require a period of assisted
ventilation, the mortality rate could be kept down to just a few percent by using appropriate
management and therapeutic strategies.

We have gained much experience in the treatment of SARS. Without being
complacent, scientists and clinicians alike are striving for more effective treatment aiming to
lower mortality and transmission rates as much as possible. This can only be achieved together with
an increased understanding of the viral structure and processes (Holmes 2003; Thiel et al 2003) and by defining the
potential targets for drug and vaccine development.

The development of vaccines and new drugs for human use usually take many years.
To expedite the development, the collaborative efforts around the world that unraveled the etiologic
agent of SARS will be continued. Previous knowledge obtained from the HIV may give us a lead (Ho D 2003; Kliger & Levanon 2003; De Groot 2003), as well as the information
known about the existing vaccines for animal coronaviruses (Clarke 2003). Three-dimensional computer
modeling of key viral proteins may also facilitate the search and design of antivirals (Anand et al 2003). On the other
hand, massive random screening and targeted searching of potential compounds by various institutions
have already tested hundreds of thousands of compounds in vitro, and have had several hits
which could be targets for further research (Abbott 2003).

While awaiting research breakthroughs, we have to rely on the existing treatment
modalities, which have been overviewed in this chapter. It is envisaged that with the early use of
efficacious antiviral agents singly or in combination, the necessity for high dose immunomodulatory
therapy may be decreased. Well-conducted randomized controlled trials on a sufficient number of
cases are necessary to clarify the effectiveness of and controversies surrounding existing treatment
regimens; however, these may not be feasible since large-scale outbreak will hopefully never be seen
again with our heightened preparedness.

If patients failed to respond (continuing high fever), with pulmonary
infiltrates involving more than one pulmonary segment, or an expanding area of consolidation was
observed, they were treated with high-dose methylprednisolone for 5-14 days (160-1000 mg daily
depending on symptoms and X-ray results: 160 mg daily if one lobe was involved; 320 mg daily if
>1 lobe; 25% needed an increase in dosage from 160 to 320-720 mg daily to maintain respiratory
physiological parameters and to control temperature).

Oxygen 3-5 L per min was given by mask if SaO2 <95% or, if patients felt
short of breath, non-invasive continuous positive airway pressure (CPAP) ventilation was
used.

If CPAP failed (SaO2 <90%), mechanical ventilation was used.

Immunoglobulins, thymic peptides or recombinant human thymus proteins were
given to some critically ill patients.